Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

ABSTRACT

Succinoylamino hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/884,462filed Jun. 20, 2001, now U.S. Pat. No. 6,469,207, which is acontinuation of application Ser. No. 09/419,816 filed Oct. 18, 1999, nowU.S. Pat. No. 6,313,345, which is a continuation application of Ser. No.09/041,016 filed Mar. 12, 1998, now U.S. 6,022,994, which was acontinuation of application Ser. No. 08/541,747 filed on Oct. 10, 1995,now U.S. Pat. No. 5,760,076, which is a divisional of application Ser.No. 08/110,912 filed Aug. 24, 1993, now U.S. Pat. No. 5,463,104, whichis a continuation-in-part of application Ser. No. 07/935,490 filed Aug.25, 1992, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to sulfonamide-containing hydroxyethylamine proteaseinhibitor compounds, a composition and method for inhibiting retroviralproteases such as human immunodeficiency virus (HIV) protease and fortreating a retroviral infection, e.g., an HIV infection. The subjectinvention also relates to processes for making such compounds as well asto intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol geneproducts are translated as proteins. These proteins are subsequentlyprocessed by a virally encoded protease (or proteinase) to yield viralenzymes and structural proteins of the virus core. Most commonly, thegag precursor proteins are processed into the core proteins and the polprecursor proteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease that processing of the gag precursor protein isprevented. Thus, attempts have been made to inhibit viral replication byinhibiting the action of retroviral proteases.

Retroviral protease inhibition may involve a transition-state mimeticwhereby the retroviral protease is exposed to a mimetic compound whichbinds to the enzyme in competition with the gag and gag-pol proteins tothereby inhibit replication of structural proteins and, moreimportantly, the retroviral protease itself. In this manner, retroviralreplication proteases can be effectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP 0 346 847; EP 0 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors,” Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990).

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200;115, GB 2,209,752, EP 0 264,795, U.S. SIRH725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. G.B. 2,200,115 also disclose certainsulfamoyl-containing hydroxyethylamine renin inhibitors. EP 0 264 795also discloses certain sulfonamide-containing renin inhibitor compounds.However, it is known chat, although renin and HIV proteases are bothclassified as aspartyl proteases, compounds which are effective renininhibitors generally cannot be predicted to be effective HIV proteaseinhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes. The subjectcompounds are characterized as succinoylamino hydroxyethylaminosulfonamide inhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof wherein:

x represents 0, 1 or 2;

t represents either 0 or 1;

R¹ represents hydrogen, —CH₂SO₂NH₂, —CO₂CH₃, —CONHCH₃, —CON(CH₃)₂,—CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONH₂, —C(CH₃)₂(SH)—C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals and amino acid side chains selected fromasparagine, S-methyl cysteine and the corresponding sulfoxide andsulfone derivatives thereof, glycine, leucine, isoleucine,allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine,histidine, norleucine, glutamine, valine, threonine, serine, o-alkylserine, aspartic acid, beta-cyano alanine, and allothreonine sidechains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, and —NO₂, —C≡N, CF₃, —OR⁹,—SR⁹ wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical;

X′ represents N, O and C(R¹⁷) where R¹⁷ represents hydrogen and alkylradicals;

Y and Y′ independently represent O, S and NR¹⁵ wherein R¹⁵ representshydrogen and radicals as defined for R³;

R⁴ represents radicals as defined by R³ except for hydrogen;

R⁶ represents hydrogen and alkyl radicals as defined for R³;

R³⁰, R³¹ and R³² represent radicals as defined for R¹, or one of R¹ andR³⁰ together with one of R³¹ and R³² and the carbon atoms to which theyare attached form a cycloalkyl radical; and

R³³ and R³⁴ independently represent hydrogen, radicals as defined for R³or R³³ and R³⁴ together with X′ represent cycloalkyl, aryl, heterocyclyland heteroaryl radicals, provided that when X′ is O; R³⁴ is absent.

A preferred class of retroviral inhibitor compounds of the presentinvention are those represented by the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof,preferably wherein the absolute stereochemistry about the hydroxy groupis designated as (R);

R¹ represents hydrogen, —CH₂SO₂NH₂, —CO₂CH₃, —CONHCH₃, —CON(CH₃)₂,—CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONH₂, —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals and amino acid side chains selected fromasparagine, S-methyl cysteine and the corresponding sulfoxide andsulfone derivatives thereof, glycine, leucine, isoleucine,allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine,histidine, norleucine, glutamine, valine, threonine, serine, asparticacid, beta-cyano alanine, and allothreonine side chains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, NO₂, —C≡N, CF₃, OR⁹ and SR⁹wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,

aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstitutedaminoalkyl radicals, wherein said substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical;

R⁴ represents radicals as defined by R³ except for hydrogen;

R³⁰, R³¹ and R³² represent radicals as defined for R¹, or one of R¹ andR³⁰ together with one of R³¹ and R³² and the carbon atoms to which theyare attached form a cycloalkyl radical; and

R³³ and R³⁴ independently represent hydrogen, radicals as defined for R³or R³³ and R³⁴ together with the nitrogen atom to which they areattached represent heterocycloalkyl and heteroaryl radicals;

Y and Y′ independently represent O, S, and NR¹⁵ wherein R¹⁵ representshydrogen and radicals as defined for R³, Preferably, Y and Y′ representO.

Yet another preferred class of compounds are those represented by theformula:

or a pharmaceutically acceptable salt, prodrug or ester thereof,preferably wherein the stereochemistry about the hydroxy group isdesignated as R, wherein Y, Y′, R¹, R², R³, R⁴, R³⁰, R³¹ and R³² are asdefined above with respect to Formula (II). Preferably, Y and Y′represent 0.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10, preferably from 1 to about 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. Theterm “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to about 8carbon atoms. Examples of suitable alkenyl radicals include ethenyl,propenyl, 1,4-butadienyl and the like. The term alkynyl, alone or incombination, means a straight-chain hydrocarbon radical having one ormore triple bonds and containing from 2 to about 10 carbon atoms.Examples of alkynyl radicals include ethynyl, propynyl, propargyl andthe like. The term “alkoxy”, alone or in combination, means an alkylether radical wherein the term alkyl is as defined above. Examples ofsuitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.The term “cycloalkyl”, alone or in combination, means a saturated orpartially saturated monocyclic, bicyclic or tricyclic alkyl radicalwherein each cyclic moiety contains from about 3 to about 8 carbonatoms. The term “cycloalkylalkyl” means an alkyl radical as definedabove which is substituted by a cycloalkyl radical containing from about3 to about 8, preferably from about 3 to about 6, carbon atoms. Examplesof such cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. The term “aryl”, alone or incombination, means a phenyl or naphthyl radical which optionally carriesone or more substituents selected from alkyl, alkoxy, halogen, hydroxy,amino, nitro, cyano, haloalkyl and the like, such as phenyl, p-tolyl,4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl,4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like. The term“aralkyl”, alone or in combination, means an alkyl radical as definedabove in which one hydrogen atom is replaced by an aryl radical asdefined above, such as benzyl, 2-phenylethyl and the like. The term“aralkoxy carbonyl”, alone or in combination, means a radical of theformula —C(O)—O-aralkyl in which the term “aralkyl” has the significancegiven above. An example of an aralkoxycarbonyl radical isbenzyloxycarbonyl. The term “aryloxy” means a radical of the formulaaryl-O— in which the term aryl has the significance given above. Theterm “alkanoyl”, alone or in combination, means an acyl radical derivedfrom an alkanecarboxylic acid, examples of which include acetyl,propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term“cycloalkylcarbonyl” means an acyl group derived from a monocyclic orbridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl;cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from abenz-fused monocyclic cycloalkanecarboxylic acid which is optionallysubstituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.The term “aralkanoyl” means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term “aroyl” means an acyl radical derived from anaromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclyalkylgroup or the like is a saturated or partially unsaturated monocyclic,bicyclic or tricyclic heterocycle which contains one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo,and the like, and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. ═N—) by oxido and which is attached via a carbonatom. The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, ora heteroaralkoxy carbonyl group or the like is an aromatic monocyclic,bicyclic, or tricyclic heterocycle which contains the hetero atoms andis optionally substituted as defined above with respect to thedefinition of heterocyclyl. Examples of such heterocyclyl and heteroarylgroups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl(e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4- or 5-benzimidazolyl, andthe like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O—COOH wherein cycloalkylalkyl has the significancegiven above. The term “aryloxyalkanoyl” means an acyl radical of theformula aryl-O-alkanoyl wherein aryl and alkanoyl have the significancegiven above. The term “heterocyclyloxycarbonyl” means an acyl groupderived from heterocyclyl-O—COOH wherein heterocyclyl is as definedabove. The term “heterocyclylalkanoyl” is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above. The term “heterocyclylalkoxycarbonyl”means an acyl radical derived from a heterocyclyl-substitutedalkane-O—COOH wherein heterocyclyl has the significance given above. Theterm “heteroaryloxycarbonyl” means an acyl radical derived from acarboxylic acid represented by heteroaryl-O—COOH wherein heteroaryl hasthe significance given above. The term “aminocarbonyl” alone or incombination, means an amino-substituted carbonyl (carbamoyl) groupderived from an amino-substituted carboxylic acid wherein the aminogroup can be a primary, secondary or tertiary amino group containingsubstituents selected from hydrogen, and alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term“aminoalkanoyl” means an acyl group derived from an amino-substitutedalkanecarboxylic acid wherein the amino group can be a primary,secondary or tertiary amino group containing substituents selected fromhydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term “halogen” means fluorine, chlorine, bromine oriodine. The term “leaving group” generally refers to groups readilydisplaceable by a nucleophile, such as an amine, a thiol or an alcoholnucleophile. Such leaving groups are well known in the art. Examples ofsuch leaving groups include N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R). However, such procedures are generally applicable,to those compounds of opposite configuration, e.g., where thestereochemistry about the hydroxyl group is (S). In addition, thecompounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedure. AnN-protected chloroketone derivative of an amino acid having the formula:

wherein P represents an amino protecting group, and R² is as definedabove, is reduced to the corresponding alcohol utilizing an appropriatereducing agent. Suitable amino protecting groups are well known in theart and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyland the like. A preferred amino protecting group is carbobenzoxy. Apreferred N-protected chloroketone isN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone. A preferredreducing agent is sodium borohydride. The reduction reaction isconducted at a temperature of from −10° C. to about 25° C., preferablyat about 0° C., in a suitable solvent system such as, for example,tetrahydrofuran, and the like. The N-protected chloroketones arecommercially available e.g. such as from Bachem, Inc., Torrance, Calif.Alternatively, the chloroketones can be prepared by the procedure setforth in S. J. Fittkau, J. Prakt. Chem., 315, 1037 (1973), andsubsequently N-protected utilizing procedures which are well known inthe art.

The halo alcohol can be used directly, as described below, or,preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula:

wherein P and R² are as defined above. Suitable solvent systems forpreparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

Alternatively, a protected amino epoxide can be prepared starting withan L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected L-amino acid esterof the formula:

wherein P¹ and P² independently represent hydrogen, benzyl andamino-protecting groups as defined above with respect to P, providedthat P¹ and P² are not both hydrogen; P³ represents a carboxylprotecting group such as methyl, ethyl, tertiary-butyl, benzyl, and thelike, and R² is as defined above.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. The resulting alcohol is thenconverted, for example, by way of a Swern oxidation, to thecorresponding aldehyde of the formula:

wherein P¹, P² and R² are as defined above. Thus, a dichloromethanesolution of the alcohol is added to a cooled (−75 to −68° C.) solutionof oxalyl chloride in dichloromethane and DMSO in dichloromethane andstirred for 35 minutes.

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

The diastereomers can be separated, e.g., by chromatography or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. For compounds having the (S) stereochemistry,a D-amino acid can be utilized in place of the L-amino acid.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of theformula:

R³NH₂

wherein R³ is hydrogen or is as defined above. The reaction can beconducted over a wide range of temperatures, e.g., from about 10° C. toabout 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic solvents, suchas, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas:

wherein P, P¹, P², R² and R³ are as described above. Alternatively, ahaloalcohol can be utilized in place of the amino epoxide,

The amino alcohol defined above is then reacted in a suitable solventwith a sulfonyl chloride (R⁴SO₂Cl) or sulfonyl anhydride in the presenceof an acid scavenger. Suitable solvents in which the reaction can beconducted include methylene chloride, tetrahydrofaran and the like.Suitable acid scavangers include triethylamine, pyridine and the like.Preferred sulfonyl chlorides are methanesulfonyl chloride andbenzenesulfonyl chloride. The resulting sulfonamide derivative can berepresented, depending on the epoxide utilized by the formulas:

wherein P, P¹, P², R², R³ and R⁴ are as defined above.

The sulfonyl halides of the formula R⁴SO₂X can be prepared by thereaction of a suitable Grignard or alkyl lithium reagent with sulfurylchloride, or sulfur dioxide followed by oxidation with a halogen,preferably chlorine. Also, thiols may be oxidized to sulfonyl chloridesusing chlorine in the presence of water under carefully controlledconditions. Additionally, sulfonic acids may be converted to sulfonylhalides using reagents such as PCl₅, and also to anhydrides usingsuitable dehydrating reagents. The sulfonic acids may in turn beprepared using procedures well known in the art. Such sulfonic acids arealso commercially available.

In place of the sulfonyl halides, sulfinyl halides (R⁴SOX) or sulfenylhalides (R⁴SX) can be utilized to prepare compounds wherein the —SO₂—moiety is replaced by an —SO— or —S— moiety, respectively.

Following preparation of the sulfonamide derivative, the aminoprotecting group P or P¹ and P² is removed under conditions which willnot affect the remaining portion of the molecule. These methods are wellknown in the art and include acid hydrolysis, hydrogenolysis and thelike. A preferred method involves removal of the protecting group, e.g.,removal of a carbobenzoxy group, by hydrogenolysis utilizing palladiumon carbon in a suitable solvent system such as an alcohol, acetic acid,and the like or mixtures thereof. Where the protecting group is at-butoxycarbonyl group, it can be removed utilizing an inorganic ororganic acid, e.g., HCl or trifluoroacetic acid, in a suitable solventsystem, e.g., dioxane or methylene chloride. The resulting product isthe amine salt derivative. Where the protecting group is a benzylradical, it can be removed by hydrogenolysis. Following neutralizationof the salt, the amine is then reacted with a succinic acid as describedbelow

To produce the succinic acid portion of the compounds of Formula I, thestarting material is a lactate of the formula:

wherein P″ represents alkyl and aralkyl radicals, such as, for example,ethyl, methyl, benzyl and the like. The hydroxyl group of the lactate isprotected as its ketal by reaction in a suitable solvent system withmethyl isopropenyl ether (1,2-methoxypropene) in the presence of asuitable acid. Suitable solvent systems include methylene chloride,tetrahydrofuran and the like as well as mixtures thereof. Suitable acidsinclude POCl₃ and the like. It should be noted that well-known groupsother than methyl isopropenyl ether can be utilized to form the ketal.The ketal is then reduced with diisobutylaluminum hydride (DIBAL) at−78° C. to produce the corresponding aldehyde which is then treated withethylidene triphenylphosphorane (Wittig reaction) to produce a compoundrepresented by the formula:

The ketal protecting group is then removed utilizing procedureswell-known in the art such as by mild acid hydrolysis. The resultingcompound is then esterified with isobutyryl chloride to produce acompound of the formula:

This compound is then treated with lithium diisopropyl amide at −78° C.followed by warming of the reaction mixture to room temperature toeffect a Claisen rearrangement ([3,3]) to produce the corresponding acidrepresented by the formula:

Those skilled in the art will recognize that variations on this schemeare possible, using either different protecting groups or reagents tocarry out the same transformations. One can also utilize other acidchlorides in place of isobutyryl chloride to prepare similar analogs.

Treatment of the acid with benzyl bromide in the presence of a tertiaryamine base, e.g., DBU, produces the corresponding ester which is thencleaved oxidatively to give a trisubstituted succinic acid:

The trisubstituted succinic acid is then coupled to the sulfonamideisostere utilizing procedures well known in the art. To produce the freeacid, the benzyl ester is removed by hydrogenolysis to produce thecorresponding acid. The acid can then be converted to the primary amideby methods well-known in the art. The resulting product is a compoundrepresented by Formula I.

An alternative method for preparing trisubstituted succinic acidsinvolves reacting an ester of acetoacetic acid represented by theformula:

where R is a suitable protecting group, such as methyl, ethyl, benzyl ort-butyl with sodium hydride and a hydrocarbyl halide (R³¹X or R³²X) in asuitable solvent, e.g., THF, to produce the corresponding disubstitutedderivative represented by the formula:

This disubstituted acetoacetic acid derivative is then treated withlithium diisopropyl amide at about −10° C. and in the presence ofPhN(triflate)₂ to produce a vinyl triflate of the formula:

The vinyl triflate is then carbonylated utilizing a palladium catalyst,e.g., Pd(OAc)₂ and Ph₃P, in the presence of an alcohol (R″OH) or water(R″=H) and a base, e.g., triethylamine, in a suitable solvent such asDMF, to produce the olefinic ester or acid of the formula:

The olefin can then be subsequently asymmetrically hydrogenated, asdescribed below, to produce a trisubstituted succinic acid derivative ofthe formula:

If R″ is not H, R″ can be removed by either hydrolysis, acidolysis, orhydrogenolysis, to afford the corresponding acid, which is then coupledto the sulfonamide isostere as described above and then, optionally, theR group removed to produce the corresponding acid, and optionally,converted to the amide.

Alternatively, one can react the sulfonamide isostere with either asuitably monoprotected succinic acid or glutaric acid of the followingstructure;

followed by removal of the protecting group and conversion of theresulting acid to an amide. One can also react an anhydride of thefollowing structure;

with the sulfonamide isostere and then separate any isomers or convertthe resulting acid to an amide and then separate any isomers.

It is contemplated that for preparing compounds of the Formulas havingR⁶, the compounds can be prepared following the procedure set forthabove and, prior to coupling the sufonamide derivative to the succinicacid portion of the molecule carried through a procedure referred to inthe art as reductive amination. Thus, a sodium cyanoborohydride and anappropriate aldehyde or ketone can be reacted with the sulfonamidederivative compound or appropriate analog at room temperature in orderto reductively aminate any of the compounds of Formulas I-III. It isalso contemplated that where R³ of the amino alcohol intermediate ishydrogen, the inhibitor compounds can be prepared through reductiveamination of the final product of the reaction between the amino alcoholand the amine or at any other stage of the synthesis for preparing theinhibitor compounds.

Contemplated equivalents of the general formulas set forth above for theantiviral compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties wherein one or more of the various R groups are simplevariations of the substituents as defined therein, e.g., wherein R is ahigher alkyl group than that indicated. In addition, where a substituentis designated as, or can be, a hydrogen, the exact chemical nature of asubstituent which is other than hydrogen at that position, e.g., ahydrocarbyl radical or a halogen, hydroxy, amino and the like functionalgroup, is not critical so long as it does not adversely affect theoverall activity and/or synthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

EXAMPLE 1

Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylamine

Part A

To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1L). The solutionwas washed sequentially with 1M potassium hydrogen sulfate, saturatedsodium bicarbonate and then saturated sodium chloride solutions. Afterdrying over anhydrous magnesium sulfate and filtering, the solution wasremoved under reduced pressure. To the resulting oil was added hexane(approx. 1L) and the mixture warmed to 60° C. with swirling. Aftercooling to room temperature, the solids were collected and washed with2L of hexane. The resulting solid was recrystallized from hot ethylacetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺298.

Part C

19.9 equivalents) in 90 mL of isopropyl alcohol was heated to reflux for3.1 h. The solution was cooled to room temperature and partiallyconcentrated in vacuo and the remaining solution poured into 200 mL ofstirring hexanes whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 11.76 g, 79% ofN[[3(S)-phenylmethylcarbamoyl) amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]amine, mp 118-122° C., FABMS: MH⁺=385.

EXAMPLE 2

Preparation of phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylaminefrom Example 1, Part C (2.0 gm, 5.2 mmol) and triethylamine (723 uL, 5.5mmol) in dichloromethane (20 mL) was added dropwise methanesulfonylchloride (400 uL, 5.2 mmol). The reaction mixture was stirred for 2hours at room temperature, then the dichloromethane solution wasconcentrated to ca. 5 mL and applied to a silica gel column (100 gm).The column was eluted with chloroform containing 1% ethanol and 1%methanol. The phenylmethyl

[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate was obtained asa white solid Anal. Calcd for C₂₄H₃₄N₂O₅S: C, 62.31; H, 7.41; N, 6.06.Found: C, 62.17; H, 7.55; N, 5.97.

EXAMPLE 3

Preparation of phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

From the reaction ofN(3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylaminefrom Example 1, Part C (1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8mmol) and benzenesulfonyl chloride (483 uL, 3.8 mmol) one obtainsphenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate. Columnchromotography on silica gel eluting with chloroform containing 1%ethanol afforded the pure product. Anal. Calcd for C₂₉H₃₆N₂O₅S: C,66.39; H, 6.92; N, 5.34. Found: C, 66.37; H, 6.93; N, 5.26.

EXAMPLE 4

Preparation of Benzyl 2,2,3(R)-trimethylsuccinate

Part A

Preparation of Methyl (S)-lactate, 2-methoxy-2-propyl ether.

To a mixture of methyl(S)-(−)-lactate (13.2 g, 100 mmol) and,2-methoxypropene (21.6 g, 300 mmol) in CH₂Cl₂ (150 ml) was added POCl₃(7 drops) at r.t. and the resulting mixture was stirred at thistemperature for 16 hours. After the addition of Et₃N (10 drops), thesolvents were removed in vacuo to give 20.0 g of (98%) desired product.

Part B

Preparation of 2(S)-hydroxypropanal, 2-methoxy-2-propyl ether.

To a solution of compound from Part A (20.0 g) in CH₂Cl₂ (100 ml) wasadded DIBAL (65 ml of 1.5M solution in toluene, 97.5 mmol) dropwise at−78° C. for 45 min., then stirring was continued at this temperature foranother 45 min. To this cold solution was added MeOH (20 ml), saturatedNaCl solution (10 ml) and allowed the reaction mixture to warm up tor.t. and diluted with ether (200 ml), MgSO₄ (150 g) was added andstirred for another 2 h. The mixture was filtered and the solid waswashed twice with ether. The combined filtrates were rotavaped to afford11.2 g (78%) of the desired aldehyde.

Part C

Preparation of 2(S)-hydroxy-cis-3-butene, 2-methoxy-2-propyl ether.

To a suspension of ethyltriphenylphosphonium bromide (28 g, 75.5 mmol)in THF (125 ml) was added KN (TMS)₂ (15.7 g, 95%, 75 mmol) in portionsat 0° C. and stirred for 1 h at the temperature. This red reactionmixture was cooled to −78° C. and to this was added a solution ofaldehyde from Part B (11 g, 75 mmol) in THF (25 ml). After the additionwas completed, the resulting reaction mixture was allowed to warm up tor.t. and stirred for 16 h. To this mixture was added saturated NH₄Cl(7.5 ml) and filtered through a pad of celite with a thin layer ofsilica gel on the top. The solid was washed twice with ether. Thecombined filtrates were concentrated in vacuo to afford 11.5 g of crudeproduct. The purification of crude product by flash chromatography(silica gel, 10:1 Hexanes/EtoAc) affording 8.2 g (69%) pure alkene.

Part D

Preparation of 2(S)-hydroxy-cis-3-butene.

A mixture of alkene from Part C (8.2 g) and 30% aqueous acetic acid (25ml) was stirred at r.t. for 1 hour. To this mixture was added NaHCO₃slowly until the pH was ˜7, then extracted with ether (10 ml×5). Thecombined ether solutions were dried (Na₂SO₄) and filtered. The filtratewas distilled to remove the ether to give 2.85 g (64%) pure alcohol,m/e=87(M+H).

Part E

Preparation of 2,2,3-trimethyl-hex-(trans)-4-enoic acid.

To a mixture of alcohol from Part D (2.5 g, 29 mmol) and pyridine (2.5ml) in CH₂Cl₂ (60 ml) was added isobutyryl chloride (3.1 g, 29 mmol)slowly at 0° C. The resulting mixture was stirred at r.t. for 2 hoursthen washed with H₂O (30 ml×2) and sat. NaCl (25 ml). The combinedorganic phases were dried (Na₂SO₄), concentrated to afford 4.2 g (93%)ester 2(S)-hydroxy-cis-3-butenyl isobutyrate. This ester was dissolvedin THF (10 ml) and was added to a 1.0M LDA soln. (13.5 ml of 2.0M LDAsolution in THF and 13.5 ml of THF) slowly at −78° C. The resultingmixture was allowed to warm up to r.t. and stirred for 2 h and dilutedwith 5% NaOH (40 ml) The organic phase was separated, the aqueous phasewas washed with Et₂O (10 ml). The aqueous solution was collected andacidified with 6N HCl to pH ˜3. The mixture was extracted with ether (30ml×3). The combined ether layers were washed with sat. NaCl (25 ml),dried (Na₂SO₄) and concentrated to afford 2.5 g (60%) of desired acid,m/e=157(M+H).

Part F

Preparation of benzyl 2,2,3(S)-trimethyl-trans-4-hexenoate.

A mixture of acid from Part E (2.5 g, 16 mmol), BnBr (2.7 g, 15.8 mmol),K₂CO₃ (2.2 g, 16 mmol), NaI (2.4 g) in acetone (20 ml) was heated at 75°C. (oil bath) for 16 h. The acetone was stripped off and the residue wasdissolved in H₂O (25 ml) and ether (35 ml). The ether layer wasseparated, dried (Na₂SO₄) and concentrated to afford 3.7 g (95%) ofbenzyl ester, m/e=247(M+H).

Part G

Preparation of benzyl 2,2,3(R)-trimethylsuccinate.

To a well-stirred mixture of KMnO₄ (5.4 g, 34, 2 mmol), H₂O (34 ml),CH₂Cl₂ (6 ml) and benzyltriethylammonium chloride (200 mg) was added asolution of ester from Part F (2.1 g, 8.54 mmol) and acetic acid (6 ml)in CH₂Cl₂ (28 ml) slowly at 0° C. The resulting mixture was stirred atthe temperature for 2 h then r.t. for 16 h. The mixture was cooled in anice-water bath, to this was added 6N HCl (3 ml) and solid NaHSO₃ inportions until the red color disappeared. The clear solution wasextracted with CH₂Cl₂ (30 ml×3). The combined extracts were washed withsat. NaCl solution, dried (Na₂SO₄) and concentrated to give an oil. Thisoil was dissolved in Et₂O (50 ml) and to this was added sat. NaHCO₃ (50ml). The aqueous layer was separated and acidified with 6N HCl to pH ˜3then extracted with Et₂O (30 ml×3). The combined extracts were washedwith sat. NaCl solution (15 ml), dried (Na₂SO₄) and concentrated toafford 725 mg (34%) of desired acid, benzyl 2,2,3(R)-trimethylsuccinate,m/e=251(M+H).

EXAMPLE 5

Preparation of methyl 2,2-dimethyl-3-methyl Succinate, (R) and (S)isomers.

Part A

Preparation of methyl 2,2-dimethyl-3-oxo-butanoate.

A 250 ml RB flask equipped with magnetic stir bar and N₂ inlet wascharged with 100 ml dry THF and 4.57 g (180 mmol) of 95% NaH. The slurrywas cooled to −20° C. and 10 g (87 mmol) methyl acetoacetate was addeddropwise followed by 11.3 ml (181 mmol) CH₃I. The reaction was stirredat 0° C. for 2 hours and let cool to room temperature overnight. Thereaction was filtered to remove NaI and diluted with 125 ml Et₂O. Theorganic phase was washed with 1×100 l 5% brine, dried and concentratedin vacuo to a dark golden oil that was filtered through a 30 g plug ofsilica gel with hexane. Concentration in vacuo yielded 10.05 g ofdesired methyl ester, as a pale yellow oil, suitable for use withoutfurther purification.

Part B

Preparation of methyl2,2-dimethyl-3-0-(trifluoromethanesulfonate)-but-3-enoate.

A 250 ml RB flask equipped with magnetic stir bar and N₂ inlet wascharged with 80 mL by THF and 5.25 ml (37.5 mmol) diisopropylamine wasadded. The solution was cooled to −25° C. (dry ice/ethylene glycol) and15 ml (37.5 mmol) of 2.5 M n-BuLi in hexanes was added. After 10 minutesa solution of 5 g (35 mmol) 1 in 8 ml dry THF was added. The deep yellowsolution was stirred at −20° C. for 10 min. then 12.4 g N-phenylbis(trifluoromethanesulfonimide) (35 mmol) was added. The reaction wasstirred @ −10° C. for 2 hours, concentrated in vacuo and partionedbetween ethyl acetate and sat. NaHCO₃. The combined organic phase waswashed with NaHCO₃, brine and conc. to an amber oil that was filteredthrough a 60 g silica gel plug with 300 mL 5% ethyl acetate/hexane.Conc. in vacuo yielded 9.0 g light yellow oil that was diluted with 65ml ethyl acetate and washed with 2×50 ml 5% aq K₂CO₃, 1×10 mL brine,dried over Na₂SO₄ and conc. in vacuo to yield 7.5 g (87%) vinyltriflate, (m/e=277(M+H) suitable for use without further purification.

PART C: Preparation of methyl 2,2-dimethyl-3-carboxyl-but-3-enoate.

A 250 ml Fisher Porter bottle was charged with 7.5 g (27 mmol) ofcompound prepared in B, 50 ml dry DMF, 360 mg (1.37 mmol) triphenylphosphine and 155 mg (0.69 mmol) Pd(II) (OAc)₂. The reaction mixture waspurged twice with N₂ then charged with 30 psi Co. Meanwhile a solutionof 20 ml dry DMF and 7.56 ml (54 mmol) NEt₃ was cooled to 0° C. to thiswas added 2.0 g (43 mmol) of 99% formic acid. The mixture was swirledand added to the vented Fisher Porter tube. The reaction vessel wasrecharged to 40 psi of CO and stirred 6 hours @ room temperature. Thereaction mixture was concentrated in vacuo and partioned between 100 mLof ethyl acetate and 75 mL 5% aq K₂CO₃. The aqueous phase was washedwith 1×40 mL additional ethyl acetate and then acidified with conc.HCl/ice. The aqueous phase was extracted with 2×70 mL of ethyl acetateand the organics were dried and conc. to yield 3.5 g (75%) whitecrystals, mp 72-75° C., identified as the desired product (m/e=173 (M+H)

Part D

Preparation of methyl 2,2-dimethyl-3-methylsuccinate, isomer #1.

A steel hydrogenation vessel was charged with 510 mg (3.0 mmol) acrylicacid, from Part C, and 6 mg Ru (acac)₂ (R-BINAP) in 10 ml degassed MeOH.The reaction was hydrogenated at 50 psi/room temperature for 12 hours.The reaction was then filtered through celite and conc. to 500 mg clearoil which was shown to be a 93:7 mixture of isomer #1 and #2,respectively as determined by GC analysis using a 50 M β-cyclodextrincolumn: 150° C.-15 min. then ramp 2° C./min.; isomer #1, 17.85 min.,isomer 2, 18-20 min.

PART E: Preparation of methyl 2,2-dimethyl-3-methylsuccinate, Isomer #2.

A steel hydrogenation vessel was charged with 500 mg (2.9 mmol) acrylicacid, Part C, and 6 mg Ru(OAc) (acac) (S-BINAP) in 10 ml degassed MeOH.The reaction was hydrogenated at 50 psi/room temperature for 10 hours.The reaction was filtered through celite and concentrated in vacuo toyield 490 mg of product as a 1:99 mixture of isomers #1 and #2,respectively, as determined by chiral GC as above.

In a similiar manner, one can use benzyl 2,2-dimethyl-3-oxo-butanoate toprepare benzyl 2,2,3-trimethylsuccinate, R and S isomers. Other methodsfor preparing succinic acids, succinates and succinamides are well knownin the art and can be utilized in the present invention.

EXAMPLE 6

Preparation of Butanediamide, N⁴-[2-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl) amino]-1-(phenylmethyl)propyl]-2,2,3-Trimethyl-,[1S-[1R*(S*),2S*]]-.

Part A

Preparation of Butanoic acid, 4-[[2-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1-(phenylmethyl)propyl]amino]-2,2,3-Trimethyl-4-oxo,phenylmethyl ester, [1S-[1R*(S*), 2S*]]-

A solution of 10.1 g (19.3 mmol) ofphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate from Example 3in 40 mL of methanol was hydrogenated over 2 g of 10%palladium-on-carbon under 50 psig of hydrogen for six hours Afterflushing with nitrogen, the catalyst was removed by filtration throughcelite and the filtrate concentrated to provide 7.41 g (99%) of2(R)-hydroxy-3-[(3-methylbutyl) (phenylsulfonyl,amino]-1(S)-(phenylmethyl)propylamine.

To a solution of 2.5 g (10.0 mmol) of benzyl 2,2,3(R)-trimethylsuccinateand 2.1 g (15.0 mmol) of N-hydroxybenzotriazole in 10 mL of anhydrousN,N-dimethylformamide (DMF) at 0° C., was added 2.1 g (11.0 mmol) of1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).After two hours, a solution of 3.9 g (10.0 mmol) of2(R)-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propylamine in 3 mL of DMF wasadded. After stirring at room temperature for sixteen hours, the solventwas removed under reduced pressure, the residue dissolved in ethylacetate and then washed with 0.2 N citric acid, 5% aqueous soduimbicarbonate, saturated brine, dried over anhydrous magnesuim sulfate,filtered and concentrated to afford 5.74 g of crude product. This waschromatographed over silica gel using 1% methanol/methylene chloride aseluent (R_(f)=0.08) to afford 3.87 g (62% yield) of the desired product,m/e=533(M+H⁺).

Part B

Preparation of butanoic acid, 4-[[2-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1-(phenylmethyl)propyl]amino]-2,2,3-trimethyl-4-oxo-[1S-[1R*(S*),2S*]]-.

A solution of 3.87 g (6.21 mmol) of benzyl ester from part A in 40 mL ofethanol was hydrogenated over 1.5 g of 10% palladium-on-carbon under 50psig of hydrogen for four hours. After flushing with nitrogen, thecatalyst was rermoved by filtration through celite and the filtrateconcentrated under reduced pressure to afford 3.24 g (98%) of desiredproduct.

Part C

Preparation of Butanediamide,N⁴-[2-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amine]-1-(phenylmethyl)propyl]-2,2,3-trimethyl-,[1S-[1R*(S*),2S*]]-.

To a solution of 3.24 g (6.1 mmol) of acid from part B and 1.86 g (12.2mmol) of N-hydroxybenzotriazole in 6 mL of anhydrous DMF at 0° C. wasadded 1.75 g (9.1 mmol) of EDC. After stirring at 0° C. for two hours,3.44 g (60.8 mmol) of 30% aqueous ammonia was added. After stirring atroom temperature for twenty hours, the solvents were removed underreduced pressure, the residue dissolved in ethyl acetate and then washedwith 0.2 N citric acid, 5% aqueous sodium bicarbonate, saturated brine,dried over anhydrous magnesium sulfate, filtered and concentrated toafford 3.75 g of crude material. This was passed through a column of 150g of basic alumina with 20:1 (v:v) methylene chloride/methanol to removeunreacted acid. The resulting product was precipitated from methylenechloride with hexane to afford 2.1 g (65%) of the desired product, m.p.110°-112° C., m/e=538 (m+Li).

EXAMPLE 7

In a manner analogous to that of the previous examples, the compoundslisted in Table 1 were prepared.

TABLE 1 Mass Determination Entry COMPOUND Formula Calcd Found 1

C₃₅H₄₆O₆N₂S 623(M + H) 623 2

C₂₈H₄₀O₆N₂S 539(M + Li) 539 3

C₂₈H₄₁O₅N₃S 538(M + Li) 538 4

C₃₄H₄₄O₆N₂S 615(M + Li) 615 5

C₂₇H₃₈O₆N₂S 525(M + Li) 525 6

C₂₇H₃₉O₅N₃S 524(M + Li) 524 7

C₃₅H₄₆O₇N₂S 645(M + Li) 645 8

C₂₈H₄₀O₇N₂S 549(M + H) 549 9

C₂₈H₄₁O₆N₃S 548(M + H) 548

EXAMPLE 8

Additional exemplary compounds of the present invention are listed inTables 2-7. These compounds could be prepared in a manner analogous tothe above Examples and according to the following general procedures.

General Procedure for the Synthesis of Amino Epoxide

Part A

To a solution of 0.226 mol of N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone in a mixture of 807 mL of methanol and 807 mL oftetrahydrofuran at −2° C., is added 1.54 equiv. of solid sodiumborohydride over one hundred minutes. The solvents are then removedunder reduced pressure at 40° C. and the residue is dissolved in ethylacetate (approx. 1L). The solution is washed sequentially with 1Mpotassium hydrogen sulfate, saturated sodium bicarbonate and is thensaturated sodium chloride solutions. After drying over anhydrousmagnesium sulfate and filtering, the solution is removed under reducedpressure. To the resulting oil is added hexane (approx. 1L) and themixture is warmed to 60° C. with swirling. After cooling to roomtemperature, the solids are collected and washed with 2L of hexane. Theresulting solid is recrystallized from hot ethyl acetate and hexane toafford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B

To a solution of 1.2 equiv. of potassium hydroxide in 968 mL of absoluteethanol at room temperature, is added 0.097 mol ofN-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. After stirring forfifteen minutes, the solvent is removed under reduced pressure and thesolids are dissolved in methylene chloride. After washing with water,drying over magnesium sulfate, filtering and stripping, one obtains awhite solid. Recrystallization from hot ethyl acetate and hexane willafford N-benzyloxycarbonyl-3 (S)-amino-1,2(S)-epoxy-4-phenylbutane.

Alternate General Procedure for the Synthesis of Amino Epoxides

Step A

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 ml) is heated to 97° C. Benzyl bromide (108.5 ml, 0.912 mol) isthen slowly added (addition time—25 min). The mixture is then stirred at97° C. for 30 minutes. The solution is cooled to room temperature andextracted with toluene (2×250 ml). The combined organic layers are thenwashed with water, brine, dried over magnesium sulfate, filtered andconcentrated to give an oil product. The crude product is then used inthe next step without purification.

Step B

The crude benzylated product of the above step is dissolved in toluene(750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) is then added at a rate to maintain thetemperature between −55° to −50° C. (addition time—1 hour). The mixtureis stirred for 20 minutes at −55° C. The reaction is quenched at −55° C.by the slow addition of methanol (37 ml). The cold solution is thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) is filtered off and washed with toluene. The solidmaterial is suspended in a mixture of toluene (400 ml) and water (100ml). The mixture is cooled to 5° C., treated with 2.5 N NaOH (186 ml)and then stirred at room temperature until the solid is dissolved. Thetoluene layer is separated from the aqueous phase and washed with waterand brine, dried over magnesium sulfate, filtered and concentrated to avolume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) arethen added to the residue upon which the alcohol product begins tocrystallize. After 30 min., an additional 50 ml hexane is added topromote further crystallization. The solid is filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof material can be isolated by refiltering the mother liquor. The solidsare combined and recrystallized from ethyl acetate (20 ml) and hexane(30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors are combined and concentrated (34 g). The residue is createdwith ethyl acetate and hexane which provides an additional 7 g (˜7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

Step C

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) is cooled to −74° C. A solution of DMSO (12.0 ml, 0.155 mol) indichloromethane (50 ml) is then slowly added at a rate to maintain thetemperature at −74° C. (addition time —1.25 hr). The mixture is stirredfor 5 min. followed by addition of a solution of the alcohol (0.074 mol)in 100 ml of dichloromethane (addition time—20 min., temp. −75° C. to−68° C.). The solution is stirred at −78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) is then added over 10 min. (temp.−78° to −68° C.) upon which the ammonium salt precipitated. The coldmixture is stirred for 30 min. and then water (225 ml) is added. Thedichloromethane layer is separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue is diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate isconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

Temperatures higher than −70° C. have been reported in the literaturefor the swern oxidation. Other Swern modifications and alternatives tothe Swern oxidations are also possible.

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) is cooled to −78° C. A 1.6 Msolution of n-butyllithium in hexane (25 ml, 0.040 mol) is then added ata rate to maintain the temperature at −75° C. (addition time—15 min.).After the first addition, additional chloroiodomethane (1.6 ml, 0.022mol) is added again, followed by n-butyllithium (23 ml, 0.037 mol),keeping the temperature at −75° C. The mixture is stirred for 15 min.Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) andn-butyllithium (5 ml, 0.008 mol) are added 4 more times over 45 min. at−75° C. The cooling bath is then removed and the solution warmed to 22°C. over 1.5 hr. The mixture is poured into 300 ml of saturated aq.ammonium chloride solution. The tetrahydrofuran layer is separated. Theaqueous phase is extracted with ethyl acetate (1×300 ml). The combinedorganic layers are washed with brine, dried over magnesium sulfate,filtered and concentrated to give a brown oil (27.4 g). The productcould be used in the next step without purification. The desireddiastereomer can be purified by recrystallization at the subsequentsulfonamide formation step.

Alternately, the product could be purified by chromatography.

General Procedure for the Synthesis of 1,3-Diamino 4-phenyl Butan-2-olDerivatives.

A mixture of the amine R³NH₂ (20 equiv.) in dry isopropyl alcohol (20mL/mmol of epoxide to be converted) is heated to reflux and then istreated with an N-Cbz amino epoxide of the formula:

from a solids addition funnel over a 10-15 minute period. After theaddition is complete the solution is maintained at reflux for anadditional 15 minutes and the progress of the reaction monitored by TLC.The reaction mixture is then concentrated in vacuo to give an oil and isthen treated with n-hexane with rapid stirring whereupon the ringopened-material precipitates from solution. Precipitation is generallycomplete within 1 hr and the product is then isolated by filtration on aBuchner funnel and is then air dried. The product is further dried invacuo. This method affords amino alcohols of sufficient purity for mostpurposes.

General Procedure for the Reaction of Amino Alcohols with SulfonylHalides or Sulfonyl Anhydrides: Preparation of Sulfonamides

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(2.0 gm, 5.2 mmol) and triethylamine (723 uL, 5.5 mmol) indichloromethane (20 mL) is added dropwise methanesulfonyl chloride (400uL, 5.2 mmol). The reaction mixture is stirred for 2 hours at roomtemperature, then the dichloromethane solution is concentrated to ca. 5mL and applied to a silica gel column (100 gm). The column is elutedwith chloroform containing 1% ethanol and 1% methanol.

Alternatively, from the reaction of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine (1.47 gm, 3.8 mmol),triethylamine (528 uL, 3.8 mmol) and benzenesulfonyl chloride (483 uL,3.8 mmol) one can obtain the appropriate (phenylsulfonyl)aminoderivative.

General Procedure for the Removal of the Protecting Groups byHydrogenolysis with Palladium on Carbon

A. Alcohol Solvent

The Cbz-protected peptide derivative is dissolved in methanol (ca.20mL/mmol) and 10% palladium on carbon catalyst is added under a nitrogenatmosphere. The reaction vessel is sealed and flushed 5 times withnitrogen and then 5 times with hydrogen. The pressure is maintained at50 psig for 1-16 hours and then the hydrogen is replaced with nitrogenand the solution is filtered through a pad of celite to remove thecatalyst. The solvent is removed in vacuo to give the free aminoderivative of suitable purity to be taken directly on to the next step.

B. Acetic Acid Solvent

The Cbz-protected peptide derivative is dissolved in glacial acetic acid(20 mL/mmol) and 10% palladium on carbon catalyst is added under anitrogen atmosphere. The reaction vessel is flushed 5 times withnitrogen and 5 times with hydrogen and then maintained at 40 psig forabout 2 h. The hydrogen is then replaced with nitrogen and the reactionmixture filtered through a pad of celite to remove the catalyst. Thefiltrate is concentrated and the resulting product is taken up inanhydrous ether and is evaporated to dryness 3 times. The final product,the acetate salt, is dried in vacuo and is of suitable purity forsubsequent conversion.

General Procedure for Removal of Boc-protecting Group with 4NHydrochloric Acid in Dioxane

The Boc-protected amino acid or peptide is treated with a solution of 4NHCl in dioxane with stirring at room temperature. Generally thedeprotection reaction is complete within 15 minutes, the progress of thereaction is monitored by thin layer chromatography (TLC). Uponcompletion, the excess dioxane and HCl are removed by evaporation invacuo. The last traces of dioxane and HCl are best removed byevaporation again from anhydrous ether or acetone. The hydrochloridesalt thus obtained is thoroughly dried in vacuo and is suitable forfurther reaction.

TABLE 2

Entry R R³ R⁴ 1 OH CH₃ C₆H₅ 2 OH i-Butyl CH₃ 3 OH i-Butyl n-Butyl 4 NH₂i-Butyl n-Butyl 5 OH i-Propyl n-Butyl 6 NH₂ i-Propyl n-Butyl 7 OH C₆H₅n-Butyl 8 OH

n-Butyl 9 OH

n-Butyl 10 NH₂

n-Butyl 11 OH

n-Butyl 12 OH i-Butyl n-Propyl 13 OH i-Butyl —CH₂CH(CH₃)₂ 14 OH

n-Butyl 15 OH

i-Propyl 16 OH

—CH₂CH₂CH(CH₃)₂ 17 OH i-Butyl —CH₂CH₃ 18 OH i-Butyl —CH(CH₃)₂ 19 OHi-Butyl

20 NH₂ i-Butyl

21 OH

—(CH₂)₂CH(CH₃)₂ 22 OH (CH₂)₂CH(CH₃)₂ —CH(CH₃)₂ 23 NH₂ i-Butyl —CH(CH₃)₂24 OH i-Butyl —C(CH₃)₃ 25 NH₂ i-Butyl —C(CH₃)₃ 26 OH

—C(CH₃)₃ 27 NH₂

—C(CH₃)₃ 28 OH —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃ 29 NH₂ —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃30 OH —CH₂C₆H₅ —C(CH₃)₃ 31 NH₂ —CH₂C₆H₅ —C(CH₃)₃ 32 OH —(CH₂)₂C₆H₅—C(CH₃)₃ 33 NH₂ —(CH₂)₂C₆H₅ —C(CH₃)₃ 34 OH n-Butyl —C(CH₃)₃ 35 OHn-Pentyl —C(CH₃)₃ 36 OH n-Hexyl —C(CH₃)₃ 37 OH

—C(CH₃)₃ 38 OH —CH₂C(CH₃)₃ —C(CH₃)₃ 39 NH₂ —CH₂C(CH₃)₃ —C(CH₃)₃ 40 OH

—C(CH₃)₃ 41 OH —CH₂C₆H₅OCH₃(para) —C(CH₃)₃ 42 OH

—C(CH₃)₃ 43 OH

—C(CH₃)₃ 44 OH —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 45 NH₂ —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 46OH —(CH₂)₄OH —C(CH₃)₃ 47 NH₂ —(CH₂)₄OH —C(CH₃)₃ 48 NH₂

—C(CH₃)₃ 49 NH₂

—C(CH₃)₃ 50 OCH₂Ph

—C₆H₅ 51 OH

—C₆H₅ 52 NH₂

—C₆H₅ 53 OCH₂Ph —CH₂C₆H₁₁ —C₆H₅ 54 OH —CH₂C₆H₁₁ —C₆H₅ 55 NH₂ —CH₂C₆H₁₁—C₆H₅ 56 OCH₂Ph —CH₂Ph —C₆H₅ 57 OH —CH₂Ph —C₆H₅ 58 NH₂ —CH₂Ph —C₆H₅ 59OCH₂Ph

—C₆H₅ 60 OH

—C₆H₅ 61 NH₂

—C₆H₅ 62 OCH₂Ph

—C₆H₅ 63 OH

—C₆H₅ 64 NH₂

—C₆H₅ 65 OCH₂Ph —CH₂CH(CH₃)₂ —CH₃ 66 OH —CH₂CH(CH₃)₂ —CH₃ 67 NH₂—CH₂CH(CH₃)₂ —CH₃ 68 OCH₂Ph —CH₂CH(CH₃)₂ —C₆H₁₁ 69 OH —CH₂CH(CH₃)₂—C₆H₁₁ 70 NH₂ —CH₂CH(CH₃)₂ —C₆H₁₁ 71 OCH₂Ph —CH₂CH(CH₃)₂

72 OH —CH₂CH(CH₃)₂

73 NH₂ —CH₂CH(CH₃)₂

74 OCH₂Ph —CH₂CH(CH₃)₂ —CF₃ 75 OH —CH₂CH(CH₃)₂ —CF₃ 76 NH₂ —CH₂CH(CH₃)₂—CF₃ 77 OCH₂Ph —CH₂CH(CH₃)₂

78 OH —CH₂CH(CH₃)₂

79 NH₂ —CH₂CH(CH₃)₂

80 OCH₂Ph —CH₂CH(CH₃)₂

81 OH —CH₂CH(CH₃)₂

82 NH₂ —CH₂CH(CH₃)₂

83 OCH₂Ph —CH₂CH(CH₃)₂

84 OH —CH₂CH(CH₃)₂

85 NH₂ —CH₂CH(CH₃)₂

TABLE 3

Entry R¹ 1 CH₂SO₂CH₃ 2 (R)-CH(OH)CH₃ 3 CH(CH₃)₂ 4 (R,S)CH₂SOCH₃ 5CH₂SO₂NH₂ 6 CH₂SCH₃ 7 CH₂CH(CH₃)₂ 8 CH₂CH₂C(O)NH₂ 9 (S)-CH(OH)CH₃ 10—CH₂C∫CH 11 —CH₂CH₃ 12 —CH₂C(O)NH₂

TABLE 4

Entry R² 1 n-Bu 2 cyclohexylmethyl 3 C₆H₅CH₂ 4 2-naphthylmethyl 5p-F(C₆H₄)CH₂ 6 p-(PhCH₂O) (C₆H₄)CH₂ 7 p-HO(C₆H₄)CH₂

TABLE 5

Entry R³ R⁴ 1 —CH₂CH(CH₃)₂ —CH(CH₃)₂ 2 —CH₂CH(CH₃)₂

3 —CH₂CH(CH₃)₂

4 —CH₂CH(CH₃)₂

5 —CH₂CH(CH₃)₂

TABLE 6

Entry R¹ R³⁰ R³¹ R³² X′ R³³ R³⁴ 1 H H H H N H H 2 H H H H O H — 3 H H HH O CH₃ — 4 CH₃ H H H N H H 5 CH₃ H H H O H — 6 H H CH₃ H N H H 7 H HCH₃ H O H — 8 CH₃ CH₃ H H N H H 9 CH₃ CH₃ H H O H — 10 CH₃ CH₃ H H OCH₂C₆H₄OCH₃ — 11 H H CH₃ CH₃ N H H 12 H H CH₃ CH₃ O H 13 H H CH₃ CH₃ OCH₂C₆H₄OCH₃ — 14 CH₃ H CH₃ H N H H 15 CH₃ H CH₃ H N H CH₃ 16 CH₃ H CH₃ HN CH₃ CH₃ 17 CH₃ H CH₃ H O H — 18 CH₃ H CH₃ H O —CH₂C₆H₅OCH₃ — 19 OH H HH N H H 20 OH H H H O H — 21 H H OH H N H H 22 H H OH H O H — 23 CH₂ H HH N H H 24 CH₂C(O)NH₂ H H H N H H 25 CH₂C(O)NH₂ H H H O H — 26CH₂C(O)NH₂ H H H O CH₃ — 27 CH₂Ph H H H N H H 28 CH₃ H CH₃ CH₃ O CH₂Ph —29 CH₃ H CH₃ CH₃ O H — 30 CH₃ H CH₃ CH₃ N H H 31 CH₃ H CH₃ CH₃ N H CH₃32 CH₃ H CH₃ CH₃ N CH₃ CH₃ 33 CH₂CH₃ H CH₃ CH₃ O H — 34 CH₂CH₃ H CH₃ CH₃N H H 35 CH₃ H CH₂CH₃ CH₂CH₃ O H — 36 CH₃ H CH₂CH₃ CH₂CH₃ N H H

TABLE 7

EXAMPLE 9

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein disclosed inhibited the HIV enzyme. Thepreferred compounds of the present invention and their calculated IC₅₀(inhibiting concentration 50%, i.e., the concentration at which theinhibitor compound reduces enzyme activity by 50%) values are shown inTable 8. The enzyme method is described below. The substrate is2-aminobenzoyl-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control isMVT-101 (Miller, M. et al, Science, 246, 1149 (1989)] The assayconditions are as follows:

Assay buffer: 20 mM sodium phosphate, pH 6.4

20% glycerol

1 mM EDTA

1 mM DTT

0.1% CHAPS

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 μM.

HIV protease is diluted in the assay buffer to a final enzymeconcentration. of 12.3 nanomolar, based on a molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10× the test concentration; 10 μl of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

TABLE 8 Entry Compound IC_(50 (nM)) 1

80 2

2 3

2 4

34 5

1 6

2 7

16 8

2 9

2

EXAMPLE 10

The effectiveness of the compounds listed in Table 8 were determined inthe above-described enzyme assay and in a CEM cell assay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based colorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods 20, 309-321 (1988). Assays wereperformed in 96-well tissue culture plates. CEM cells, a CD4⁺ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells was dispensed into each well ofthe tissue culture plate. To each well was added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells were incubated at 37° C. for 1 hour. A frozen culture of HIV-1was diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀ =the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)was added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells received culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound was determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contained the following experiments:

Cells Drug Virus 1. + − − 2. + + − 3. + − + 4. + + +

In experiments 2 and 4 the final concentrations of test compounds were1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxyinosine(ddI) was included as a positive drug control. Test compounds weredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration did not exceed 1.5% in any case. DMSO was addedto all control wells at an appropriate concentration.

Following the addition of virus, cells were incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. on day 7, post-infection, the cells ineach well were resuspended and a 100 μl sample of each cell suspensionwas removed for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded to each 100 μL cell suspension, and the cells were incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample was added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and sampleswere incubated overnight. The absorbance at 590 nm was determined foreach sample using a Molecular Devices microplate reader. Absorbancevalues for each set of wells is compared to assess viral controlinfection, uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

TABLE 9 Entry Compound IC₅₀ (nm) EC₅₀ (nm) TD₅₀ (nm) 1

2 15 2

2 9 60,000 3

1 42 220,000 4

2 5 62,000 5

2 27 200,000 6

2 5 58,000

Utilizing the procedures set forth above in the examples along with thegeneral description, it is contemplated-that the compounds listed belowcould be prepared and that such compounds would have activities as HIVprotease inhibitors substantially similar to the activities of thecompounds set forth in the examples.

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit other strainsof HIV such as HIV-2, and other viruses such as human T-cell leukemiavirus, simian immunodeficiency virus, feline leukemia virus, respiratorysyncitial virus, hepadnavirus, cytomegalovirus and picornavirus. Thus,the subject compounds are effective in the treatment and/or proplylaxisof retroviral infections.

Compounds of the present can possess one or more asymmetric carbon atomsand are thus capable of existing in the form of optical isomers as wellas in the form of racemic or nonracemic mixtures thereof. The opticalisomers can be obtained by resolution of the racemic mixtures accordingto conventional processes, for example by formation of diastereoisomericsalts by treatment with an optically active acid or base. Examples ofappropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid and then separation of themixture of diastereoisomers by crystallization followed by liberation ofthe optically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomericaly purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,mechanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, cartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this 3S invention is selected in accordance witha variety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT or with N-butyl-1-deoxynojirimycin for theprophylasis and/or treatment of AIDS. When administered as acombination, the therapeutic agents can be formulated as separatecompositions which are given at the same time or different times, or thetherapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound represented by the formula:

or a pharmaceutically acceptable salt or ester thereof, wherein: xrepresents 0, 1 or 2; t represents either 0 or 1; X′ represents —N(R³⁴)—or —O—; or R³³—X′— represents cycloalkyl or aryl radicals; Y and Y ′each independently represents O or S; R¹, R³⁰, R³¹ and R³² eachindependently represent hydrogen, —OH, —(CH₂)C(O)CH₂, —CH₂SO₂NH₂,—CO₂CH₃, —CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃) ₂, —CONH₂,—C(CH₃)₂(SH)₃—C(CH₃)₇(SCH₁), —C(CH₃)₂(S(O)CH₃), —C(CH₃)₂(S(O)₃CH₃),alkyl, haloakyl, alkenyl, alkynyl, aralkyl or cycloakyl radicals or theside chain of the amino acid asparagine, S-methyl cysteine or thecorresponding sulfoxide or sulfoxide derivatives thereof, leucine,isoleucine, allo-isoleucine, tert-leucine, phenylalanine, omithine,alanine, norleucine, glutamine, valine, threonine, serine, o-alkylserine, aspartic acid, beta-cyno alanine or allothreonine; or R³⁰ andR³² together with the carbon atoms to which they are attached form acycloalkyl radical; R² represents alkyl, aryl, cycloalkyl,cycloalkylalky or aralkyl radicals, which radicals are optionallysubstituted with halogen, alkyl, —NO₂, —CN, —CF₃, —OR⁹ or —SR⁹ radicals,wherein R⁹ represents hydrogen or alkyl radicals; R³, R³³, and R³⁴ eachindependently represent hydrogen, alkyl, haloakyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl oraminoalkyl radicals or N-mono- or N,N-disubstituted aminoalkyl radicals,wherein said substituents are alkyl, aryl, aralkyl, cycloalkyl orcycloalkylalkyl radicals; R⁴ represents alkyl, haloalkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,hetercycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl, or aryl or aralkyl radicals substituted withone or more substituents selected from alkyl, alkoxy, halogen, hydroxy,amino, nitro, cyano, and haloalkyl; R⁴ represents hydrogen or alkylradicals; and wherein alkyl, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 to 8carbon atoms; alkenyl, alone or in combination. means a straight-chainor branched-chain hydrocarborn radial having one or more double bondsand containing from 2 to 8 carbon atoms; alkynyl, alone or incombinaticm, means a straight-chain hydrocarbon radical having one ormore triple bonds and containing from 2 to 10 carbon atoms; cycloalkyl,alone or in combination, means a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from 3 to 8 carbon atoms; and aryl, alone or incombination, means a phenyl or napbthyl radical which is optionallysubstituted with one or more alkyl, alkoxy, halogen, hydroxy, amino,acetylamino, nitro, cyano or haloalkyl radicals.
 2. The compound ofclaim 1 represented by the formula:

or a pharmaceutically acceptcblc salt or ester thereof, wherein: trepresents either 0 or 1; X′ represents —N(R³⁴)— or —O—; or R³³—X′—represents cycloalkyl or aryl radicals; R¹, R³⁰, R³¹ and R³² eachindependently represent hydrogen, —OH, —(CH₂)C(O)CH₂, —CH₂SO₂NH₂,—CO₂CH₃, —CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONH₂,—C(CH₃)₂(SH)₃ —C(CH₃)₂(SCH₃), —C(CH₃)₂(S(O)CH₃), —C(CH₃)₂(S(O)₃CH₃),alkyl, haloakyl, alkenyl, alkynyl, aralkyl or cycloakyl radicals or theside chain of the amino acid asparagine, S-methyl cysteine or thecorresponding sulfoxide or sulfoxide derivatives thereof, leucine,isoleucine, allo-isoleucine, tert-leucine, phenylalanine, omithine,alanine, norleucine, glutamine, valine, threonine, serine, o-alkylserine, aspartic acid, beta-cyno alanine or allothreonine; or R³⁰ andR³² together with the carbon atoms to which they are attached form athree to six-membered cycloalkyl radical; R² represents alkyl, aryl,cycloalkyl, cycloalkylalky or aralkyl radicals, which radicals areoptionally substituted with halogen, alkyl, —NO₂, —CN, —CF₃, —OR⁹ or—SR⁹ radicals, wherein R³ represents hydrogen or alkyl radicals; R³,R³³, and R³⁴ each independently represent hydrogen, alkyl, haloakyl,alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloaikyl,cycloalkylalkyl, aryl, aralkyl or aminoalkyl radicals or N-mono- orN,N-disubstituted aminoalkyl radicals, wherein said substituents arealkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl radicals; and R⁴represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, hetercycloalkyl, heteroaryl,hderocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl, or arylor aralkyl radicals substituted with one or more substituents selectedfrom alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, andhaloalkyl.
 3. A pharmaceutically composition comprising the compound ofclaim 2 and a pharmaceutically acceptable carrier.
 4. The compound claim2, or a pharamaceutically acceptable salt or ester thereof, wherein trepresents either 0 or 1; X′ represents —O—; R³, R³⁰, R³¹ and R³² eachindependently represent hydrogen, —OH, —(CH₂)C(O)CH₂, —CH₂SO₂NH₂,—CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONH₂,—C(CH₃)₂(SH)₃—C(CH₃)₇(SCH₁), —C(CH₃)₂(S(O)CH₃), —C(CH₃)₂(S(O)₂CH₃),alkyl, alkenyl, alkynyl or aralkyl radicals, or R³⁰ and R³² togetherwith the carbon atoms to which they are attached form a three tosix-membered cycloakyl radical; R¹ represents alkyl, cycloalkylalkyl oraralkyl radicals; which radicals are optionally substituted withhalogen, —OR⁹ or —SR⁹ radicals, wherein R⁹ represents hydrogen or alkylradicals; R³ represents alkyl, haloalkyl, alkenyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkyLalkyl, aryl or aralkyl radicals; R⁴represents alkyl, haloalkyl, alkenyl, hydroxyalkyl, alkoxyalkyl,cyecloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl, or aryl oraralkyl radicals substituted with one or more substituents selected fromalkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, and haloalkyl; andR³³ represents hydrogen, alkyl, haloalkyl, alkenyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl radicals. 5.The compound of claim 4, or a pharmaceutically acceptable salt or esterthereof, wherein t is 0; X represents —O—; R³, R³⁰, R³¹ and R³² eachindependently represent hydrogen, —OH, —(CH₂)C(O)CH₂, —CH₂SO₂NH₂,—CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONH₂,—C(CH₃)₂(SH)₃—C(CH₃)₂(SCH₂), —C(CH₃)₂(S(O)CH₃), —C(CH₃)₂(S(O)₂CH₃),alkyl, alkenyl, alkynyl or aralkyl radicals; R³ represents alkyl,cycloalkylalkyl or aralkyl radicals, which radicals are optionallysubstituted with halogen, —OR⁹ or S⁹ radicals, wherein R⁹ representshydrogen or methyl radicals; R⁹ represents alkyl, haloalkyl, aikenyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkylradicals; R⁴ represents alkyl, haloalkyl, alkenyl, hydroxyalkyl,alkoxyalkyl, cyecloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl, oraryl or aralkyl radicals substituted with one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, andhaloalkyl; and R³³ represents hydrogen, alkyl, cycloalkylalkyl oraralkyl radicals.
 6. The compound of claim 5, or a pharmaceuticallyacceptable salt or ester thereof, wherein t is 0; X′ represents —O—; R¹,R³⁰, R³¹ and R³² each independently represent hydrogen or alkylradicals; R² represents alkyl, cycloalkylalkyl or aralkyl radicals,which radicals are optionally substituted with halogen, —OR⁹ or SR⁹radicals, wherein R⁹ represents hydrogen or methyl radicals; R³represents alkyl, cycloalkyl, cycloalkyalkyl, aryl or aralkyl radicals;R⁴ represents heteroaryl, aryl, aralkyl, or aryl or aralkyl radicalssubstituted with one or more substituents selected from alkyl, alkoxy,halogen, hydroxy, amino, nitro, cyano, and haloalkyl alkyl or arylradicals; and R³³ represents hydrogen, alkyl or aralkyl radicals.
 7. Thecompound of claim 6, or a pharmaceutically acceptable salt or esterthereof, whercin t is 0; X′ represents —O—; R¹, R³⁰, R³¹ and R³² eachindependently represent hydrogen, methyl or ethyl radicals; R²represents CH₃SCH₂CH₂—, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl or cyclohexcylmethyl radicals; R³ represents n-pentyl,n-hexyl, n-propyl, i-butyl, neo-pentyl, i-amyl, n-butyl, benzyl,para-fluombcnzyl, para-methoxybenzyl, para-methylbenzyl,2-naphthylmethyl, cylohexylmethyl or cyclohexyl radicals; R⁴ representsheteroaryl, aryl, or aryl substituted with one or more substituentsselected from alkoxy, hydroxy, amino, nitro, cyano, and haloalkyl alkylor aryl radicals; and R³³ represents hydrogen, methyl, benzyl or(4-methoxyphenyl)methyl radicals.
 8. The compound of claim 7 wherein R⁴represents heteroaryl, aryl, or aryl substituted with one or moresubstituents selected from alkoxy, amino, or nitro radicals.
 9. Thecompound of claim 8 wherein R³¹ is hydrogen or methyl.
 10. The compoundof claim 9 which is


11. The compound of claim 1 represented by the formula:

or a pharniaccutically acceptable salt prodrug or ester thereof, whereinrepresents either 0 or 1; Y and Y′ each independently represent O or S;R¹, R³⁰, R³¹ and R³² each independently represent hydrogen, —OH,—(CH₂)C(O)CH₂, —CH₂SO₂NH₂, —CO₂CH₃, —CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃,—CH₂C(O)N(CH₃)₂, —CONH₂, —C(CH₃)₂(SH)₃ —C(CH₃)₂(SCH₃),—C(CH₃)₂(S(O)CH₃), —C(CH₃)₂(S(O)₃CH₃), alkyl, haloakyl, alkenyl, alkynylor cycloalkyl radicals, or the side chain of the amino acid asparagine,S-methyl cysteine or the corresponding sulfoxide or sulfone derivativesthereof, leucine, isoleucine, allo-isoleucine, tert-leucine,phenylalanine, omithine, alanine, norleucine, glutamine, valine,threonine, serine, aspartic acid, beta-cyano alanine or allotheonine; orR³⁴ and R³² together with the carbon atoms to which they are attachedform a cycloalkyl radical; R² represents alkyl, aryl, cycloalkyl,cycloalkylalkyl or aralkyl radicals, which radicals are optionallysubstituted with halogen, alkyl, —NO₂, —CN, —CF₃, —OR⁹ or —SR⁹ radicals,wherein R⁹ represents hydrogen or alkyl radicals; R¹, R³³, and R³⁴ eachindependently represent hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl oraminoalkyl radicals or N-mono- or N,N-disubstituzed aminoalkyl radicals,wherein said substituents are alkyl, aryl, aralkyl, cycloalkyl orcycloalkylalkyl radicals; R⁴ represents alkyl, haloalkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heternaryl, heterocycloalkylalkyl, aryl, aralkyl,hetenaralkyl, amnioalkyl, or aryl or aralkyl radicals substituted withone or more substituents selected from alkyl, alkoxy, halogen, hydroxy,amino, nitro, cyano, and haloalkyl.
 12. A pharmaceutical compositioncomprising a compound of claim 11 and a pharamaceutically acceptablecarrier.
 13. The compound of claim 11 or a pharmaceutically acceptablesalt or ester thereof, wherein t represents either 0 or 1; R¹, R³⁰, R³¹and R³² each independently represent hydrogen, —OH, —(CH₂)C(O)CH₂,—CH₂SO₂NH₂, —CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂,—CONH₂, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₂), —C(CH₃)₂(S(O)CH₃), —C(CH₃)₂(S(O)₂CH₃), alkyl, alkenyl, alkynyl or aralkyl radicals; or R³² and R³³together with the carbon atoms to which they are attached form a threeto six-membered cycloalkyl radical; R² represents alkyl, aryl,cycloalkyl, cycloalkylalkyl or aralkyl radicals, which radicals areoptionally substituted with halogen, alkyl, —NO₂, —CN, —CF₃, —OR⁹ or—SR⁹ radicals, wherein R⁹ represents hydrogen or alkyl radicals;R³represents alkyl, haloalkyl, alkenyl, hydroxyalkly, alkoxyalkl,cycloalkyl, cycloakylalkyl, aryl or aralkyl radicals; R⁴ representsalkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heternaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, amnioalkyl, or arylor aralkyl radicals substituted with one or more substituents selectedfrom alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, andhaloalkyl, and R³³ and R³⁴ each represent hydrogen, alkyl, alkenyl,alkynyl, hydroxalkyl, alkoxyalkyl, cycloalkyl, cycloakylalkyl, aryl,aralkyl, or aminoalkyl radicals.
 14. The compound of claim 13, or apharmaceutically acceptable salt or ester thereof, wherein t is 0; R¹,R³⁰, R³¹ and R³² each independently represent hydrogen, —OH,—(CH₂)C(O)CH₂, —CH₂SO₂NH₂, —CONHCH₃, —CON(CH₃)₂, —CH₂C(O)NHCH₃,—CH₂C(O)N(CH₃)₂, —CONH₂, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₂),—C(CH₃)₂(S(O)CH₃), —C(CH₂)₂(S(O)₂ CH₃), alkyl, alkenyl, alkynyl oraralkyl radicals, R² represents alkyl, cycloalkylalkyl or aralkylradicals, which radicals are optionally substituted with halogen, —OR⁹or —SR⁹ radicals, wherein R⁹ represents hydrogen or methyl radicals; R³represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkylradicals; R⁴ represents heteroaryl, aryl, aralkyl, or aryl or aralkylradicalc substituted with one or more substituents selected from alkyl,alkoxy, halogen, hydroxy, amino, nitro, cyano, and haloalkyl alkyl oraryl radical; and R³³ and R³⁴ each independently represent hydrogen,alkyl, hydroxyakkyl, alkoxyalkyl, aryl, aralkyl, or aminoalkyl radicals.15. The compound of claim 14, or a pharmaceutically acceptable salt orester thereof, wherein t is 0; R¹ represents hydrogen, alkyl of 1 to 4carbon atoms, alkenyl of 3 to 8 carbon atoms or aralkyl radicals; R²represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicalsare optionally substituted with halogen, —O⁹ or —SR⁹ radicals, whereinR4 represents hydrogen or methyl radicals; R³ represents alkyl,cycloalkyl, cycloalkyl alkyl, aryl or aralkyl radicals; R⁴ representsheteroaryl, aryl, or aryl substituted with one or more substituentsselected from alkoxy, hydroxy, amino, nitro, cyano, and haloalkyl alkylor aryl radicals; R³⁰, R³¹ and R32 each independently represent hydrogenor alkyl radicals; and R³³and R³⁴ each independently represent hydrogen,alkyl, or aminoalkyl radicals.
 16. The compound of claim 15, or apharmaceutically acceptable salt or ester thereof, wherein t is 0; R¹represents hydrogen, methyl ethyl, iso-propyl, propargyl, tert-butyl,sec-butyl, benzyl or phenylpropyl radicals; R² CH₂SCH₁CH₂—, iso-butyl),n-butyl, benzyl, 4-fluorobenzyl, 2-naphthylmethyl or cyclohexylmethylradicals; R³ represents n-pentyl, n-hexyl, n-propyl, i-butyl,neo-pentyl, i-amyl, n-butyl, benzyl, para-fluorobenzyl,para-methoxybenzyl, para-methylbenzyl, 2-naphthylmethyl,cyclohexylmethyl or cyclohexyl radicals; R⁴ represent heteroaryl, aryl,or aryl substituted with one or more substituent selected from alkoxy,amino, or nitro radicals; R³⁰, R³¹ and R³² each independently representhydrogen, methyl or ethyl radicals; and R³² and R³³ each independentlyrepresent hydrogen, methyl, or methylamino radicals.
 17. The compound ofclaim 16 which is


18. A method of inhibiting a retrovirus protease comprisingadministering a protease inhibiting amount of a composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier.
 19. Themethod of claim 18 wherein the retrovirus protease is HIV protease. 20.A method of treating AIDS comprising administering an effective amountof a composition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.